N-(bicycloamino-alkanoyl)-anilines

ABSTRACT

Compounds of the class of N-(bicycloamino-alkanoyl)-anilines useful as local anesthetic and anti-arrhythmic agents.

United States Patent Hermans et al.

[ N-(BICYCLOAMINO-ALKANOYL} ANILINES [72] Inventors: Hubert Karel [hasHex-mans, Beerse; Al-- lonsus Gillielmus Knaepe, l-lerentals; Joanne:Joeephns Maria Wlllems, Turnhout, all of Belgium [73] Assignee: JansenPharmaceutlca NV.

[22] Filed: Sept. 9, 1970 [2!] Appl. No.: 70,878

[52] U.S. CL ..260/287 R, 260/283 R, 260/286 R,

260/293.54, 260/562 B, 424/258, 424/267 [51 Int. Cl. ..C07d 33/06, C07d39/00 [58] Field 0! Search ..260/287, 293.54, 293.26

[56] References Cited UNITED STATES PATENTS 2,851,494 9/1958 Ehrhart..260/287 R [451 July 25,1972

V. Braun et al., Berichte Vol. 61b, p. 1,423- 1,431 (1928) PrimaryExaminerDonaId G. Daus Attorney-Salvatore R. Conte, Herbert I. Shermanand Robert L. Minier [57] ABSTRACT Compounds of the class of N-(bicycloamino-alkanoynanilines useful as local anesthetic andanti-arrhythmic agents.

15 Claim, No Drawings 1 N-(BICYCLOAMINO-ALKANOYL)-ANILINES SUMMARY OFTHE INVENTION An object of this invention is to provide a new'class ofaminoalkyl anilides, in particular, N-(bicycloaminoalkanoyl)- anilines,which compounds possess anti-arrhythmic activity and local anestheticproperties similar in action to lidocaine. The subject compounds differfrom the prior art aminoalkyl anilides in having a bicycloanino moietyas the amino function.

DESCRIPTION OF THE PREFERRED EMBODIMENTS:

The novel N-(bicycloamino-alkanoyl)-anilines of this invention may bestructurally represented by the formula:

( ZIn wherein R and R are each a member selected from the groupconsisting of methyl and chloro; Alk is a member selected from the groupconsisting of CI-l and CH CI-I and n is a whole integer from 1 to 3. Thepharmacologically active acid addition salts of (I) are also includedwithin the scope of this invention.

Among the preferred species herein are those compounds of formula (I)wherein Alk is CI-I CH and, more preferably, wherein Alk is CI-I,CH andn is l or 2. The single most preferred species is the compound:trans-6'-chloro-2,3,4,4a,5,6,7,7a-octahydro-lI-l-l-pyrindine-lpropiono-o-toluidide,including its resolved and enantiomorphs.

The subject compounds (I) are prepared by the condensation of anappropriately selected reactive ester of an alkanol of the formula:

@NH-CO-Alk-OH such as a halo compound of the formula:

B1 (II) wherein Alk, R and R are as previously described and X is halo,preferably chloro, with an appropriate bicycloamine of the formula:

(III) The compounds of formula (I) and of formula (III), due to thehydrogen atoms present at the bridged carbon atoms of the bicycloaminomoiety, may obviously occur in stereochemical relationship as trans andcis isomers. In the cisisomer, both hydrogens are on the same side ofthe molecule, and in the trans-isomer, the hydrogens are on oppositesides of the molecule. Thus, depending upon the cis-trans nature of thestarting bicycloamine (III), the corresponding nature of the finalproduct (I) will -be determined.

The organic bases of formula (I) may be converted to the correspondingpharmaceutically acceptable acid addition salts by reaction with anappropriate inorganic acid, such as, for example, hydrochloric,hydrobromic, hydriodic, sulfuric and the like acids, or with anappropriate organic acid, such as, for example, acetic, propionic,glycolic, lactic, oxalic, malonic, tartaric, citric, sulfamic, ascorbicand the like acids. In turn, the salts of formula (l) may be convertedto the corresponding base form by conventional treatment with suitablealkali.

The compounds of formula (III) have been previously described in theliterature. For the most part, the formula (11) starting materials havebeen described in the literature heretofore. To the extend they are not,the formula (II) compounds are readily obtained by the condensation ofan appropriate aniline of formula (IV) with an appropriatew-halo-alkanoyl halide of formula (V), preferably the chloride, inglacial acetic acid. Upon addition of aqueous sodium acetate, thedesired compound (II) precipitates.

H 0 Ac NH1 01-0 0-Alkx NaOAc R1 (IV) (V) R @4014: o-nm-x R,

The novel aminoalkyl anilides (I) of this invention and thetherapeutically active acid addition salts thereof have usefulpharmacological properties and pharmaceutical applications in view oftheir anti-arrhythmic and local anesthetic properties.

With regard to anti-arrhythmic I activity, the following method is usedto determine the ability of the particular compound to markedly decreaseventricular arrhythmia in laboratory animals (dogs). Ligation of theanterior descendens branch is carried out under neuroleptanalgesia [1cc. par 20 lbs. body weight of fentanyl (0.4 mg/cc.) and droperidol (20mg/cc.)]. About 16 hours later, the dogs exhibit a multifocalventricular arrhythmia which is recorded. During the test the dogs arecurarized and ventilated. After a control period of 30 minutes, thecompound to be tested is administered i.v. Using v an initial dose ofabout 2.5 to 5.0 mg/kg body weight, followed by a second dose of 5.0mg/kg 30 minutes later, a marked decrease or disappearance of theventricular arrhythmia is observed with the compounds of formula (I) inbase or salt form. In general, such response is observed to last forperiods of about 0.5 4.0 hours.

In testing for anesthetic activity, male Wistar rats weighing about -205grams are kept in metal cages and fasted for 16 hours before the startof the experiment, water being available ad libitum. The rats are thenput into individual restraining triangular cages and the lower 5 cm.portion of the tail is marked with a black pencil. Immediatelythereafter the pretreatment reaction time of each rat is measured in 0.5second units with a stopwatch by immersing the lower 5 cm. portion ofthe tail in water at 55 C. The endpoint is the typical tail withdrawalresponse and the cut off time is 10 seconds. Normal reaction time ofcontrol animals never exceeds 6 seconds. Each rat is then given twoinjections in the base of the tail of 0.1 ml. soluof each solution isbetween 6.5 and 7.3. Compounds that cannot be dissolved in saline at therequired concentration and at pH 6.5-7.3 are not tested. Thepost-treatment reaction times of the tail withdrawal reflex are measuredat different time intervals (from 1 to 240 minutes) after localinjection; a positive response is said to have occurred if the reactiontime exceeds 10 seconds. The onset of action is the time (in minutes)after treatment at which such a positive response is observed the firsttime and the duration of action is the time (in minutes) until nopositive responses occur. A minimum of three animals are used for eachcompound and the median value of the three is recorded. The compounds offormula (1) and salts thereof suitable for testing hereunder (i.e.,meeting the concentration and pH parameters) are found to have an onsetof action of 5 minutes and a duration of action ranging from about 10minutes at a dose level of 0.5 mg/rat. In contrast, the

reference local anesthetic, lidocaine, was found to be inactive at 0.5mg/rat. To have a pronounced anesthetic effect (i.e., reaction time of10 seconds) a dosage concentration of 2 mg/rat was found necessaryfor'lidocaine. Among the subject compounds having local anestheticactivity are the following:

The following examples are intended to illustrate, but not to limit, thescope of the present invention. Unless otherwise stated, all parts areby weight.

EXAMPLE I A mixture of 6.5 parts of 2-ch1oroaceto-2,6'-xylidide, 3.75parts of trans-octahydro-ll-Ll-pyrindine hydrochloride, 4.5 parts ofsodium carbonate, 0.5 parts of potassium iodide and 160 parts of4-methyl-2-pentanone is stirred and refluxed overnight. The reactionmixture is cooled and water is added. The organic layer is separated,dried, filtered and evaporated. The solid residue is boiled indiisopropylether with activated charcoal. The latter is filtered offover hyflo and after cooling the filtrate to room temperature, theproduct is crystallized. It

is filtered off, washed with petroleumether, and dried, yieldingtrans-2,3 ,4,4a,5 ,6,7,7a-octahydro- 1 PH -pyrindine-1 -aceto-2',6'l32.7 C.

EXAMPLE II A mixture of 7.2 parts of 2,6-dichloroaceto-o-toluidide, 3.75parts of trans-octahydro-lH-l-pyrindine hydrochloride, 4.5 parts ofsodium carbonate, 0.5 parts of potassium iodide and 160 partsof4-methyl-2-pentanone is stirred and refluxed overnight. The reactionmixture is cooled and water is added. The organic layer is separated,dried, filtered and evaporated. The residue is taken up indiisopropylether and boiled with activated charcoal. The solution isfiltered over hyflo and the filtrate is acidified with an excess of2-propanol previously satu-' rated with gaseous hydrogen chloride. Afterdilution with diisopropylether and cooling to room temperature, thesolid salt is crystallized. it is filtered off, washed withdiisopropylether, and recrystallized twice from a mixture of 2- propanoland diisopropylether, yielding trans-6'-ch1oro- 2,3,4,4a,5,6,7,7a-octahydro- 1 H- l -pyrindine- 1 -aceto-otoluidide hydrochloride;m.p. 187.5 C.

EXAMPLE III A mixture of 6.3 parts of 2-chloroaceto-2,6-xy1idide, 5

parts of trans-decahydroquinoline hydrochloride, 4.5 parts of sodiumcarbonate, 0.1 parts of potassium iodide and 200 parts of4-methy1-2-pentanone is stirred and refluxed for 20 hours. The reactionmixture is cooled and water is added. The organic layer is separated,dried, filtered and evaporated. The solid residue is crystallized twicefrom a mixture of petroleumether and diisopropylether, yieldingtrans-3,4,4a,5,6,7,8,8aoctahydrol(21-l)quinolineaceto-2,6'-xylidide;m.p. l25.5 C.

EXAMPLE IV A mixture of 7 parts of 3-chloropropiono-2',6-xylidide, 3.75parts of trans-octahydro-lH-l-pyrindine hydrochloride, 5.6 parts ofsodium carbonate, 0.2 parts of potassium iodide and 160 parts of4.-methyl-2-pentanone is stirred and refluxed for 70 hours. The reactionmixture is cooled and water is added. The organic layer is separated,dried, filtered and evaporated. The oily residue is taken up indiisopropylether and extracted with a diluted hydrochloric acidsolution. The aqueous acid phase is alkalized with sodium hydroxidesolution and the product is extracted with diisopropylether. The organicextract is dried, filtered and evaporated. From the oily free base,trans-2,3,4,4a, ,-5,6,7,7a-octahydro-ll-i-l-pyrindine by treatment with2-propanol previously saturated with gaseous hydrogen chloride. Thecrude solid salt is filtered off,

dried overnight at C. in vacuo and-recrystallized from a mixture of2-propanol and acetone, yielding trans-2,3,4,4a,5,6,7,7a-octahydro-lH-l-pyrindine-l-propiono-2,6' -xy1ididehydrochloride hydrate; m.p. 205.5 C.

EXAMPLE V A mixture of 7.8 parts of 3,6-dichloropropiono-o-to1uidide,3.75 parts of trans-octahydro-lH-l-pyrindine hydrochloride,

5.6 parts of sodium carbonate,-0.5 parts of potassium iodide and partsof 4-methy1-2-pentanone is stirred and refluxed for 70 hours. Thereaction mixture is. cooled and water is added. The organic layer isseparated, dried, filtered and evaporated. The residue is taken up indiisopropylether, stirred with activated charcoal, filtered over hyfloand the filtrate is evaporated again. The residue is crystallized fromdiisopropylether, yielding trans-6'-chl0r0-2,3,4,4a,5,6,7,7aoctahydroll-il -pyrindinel -propiono-o-to1uidide; m.p. l04.lC.

EXAMPLE VI A mixture of 7.8 parts of 3,6-dichloropropiono-o-toluidide,3.7 parts of cis-octahydro-lH-l-pyrindine hydrochloride, 7.5 parts ofsodium carbonate, 0.1 parts of potassium iodide and 200 parts of4-methyl-2-pentanone is stirred and refluxed for 30 hours. The reactionmixture is cooled and water is added.

The organic layer is separated, dried, filtered and evaporated. Theresidue is taken up in diisopropylether and the solution is acidifiedwith an excess of 2-propano1 previously saturated with gaseous hydrogenchloride. The crystallized salt'is filtered off and recrystallized froma mixture of acetone and diisopropylether, yielding cis-6'-chloro-2,3,4,4a,5,6,7,7a-octahydro- 1 1-1-1 -pyrindinel -propiono-o-to1uididehydrochloride; m.p. 190.7 C.

EXAMPLE VII equivalent quantities of the appropriate starting materialof 5 formula (II) and the appropriate bicycloamine of formula (Ill), thelatter in the cis or trans form as indicated by the final product:trans-2',6'-dichloro-3,4,4a,5,6,7,8,8a-octahydrol(2H)quinolinepropionanilidehydrochloride hydrate, m.p. 20l.2 C.; andtrans-6-chloro-3,4,4a,5,6,7,8,8a-octahydro-l (2H)quinolineaceto-o-toluidide hydrochloride hemihydrate, m.p. 2l0.9 C.

EXAMPLE VIII A mixture of 8.3 parts of 3,2,6-trichloropropionanilide,3.75 parts of trans-octahydro-lI'I-I-pyrindine hydrochloride, 5 parts ofsodium hydrogen carbonate and 160 parts of denatured ethanol is stirredand refluxed overnight. The reaction mixture is cooled and chloroform isadded. The whole is filtered and the filtrate is evaporated. The residueis taken up in diisopropylether, boiled with activated charcoal,filtered over hyflo and the filtrate is evaporated again. The residue isdissolved in diisopropylether and after standing overnight at 20 C., theproduct is crystallized. It is filtered off, washed withdiisopropylether and dried, yielding trans-2,6'-dichloro- 2 ,3 ,4,4a,5,6,7,7a-octahydro-l l-I- l -pyrindinel -propionanilide; m.p. 117.4 C.

EXAMPLE IX A. A mixture of 7 parts of 3-chloropropiono-2,6'-xylidide,3.75 parts of cis-octahydro-lI-I-l-pyrindine hydrochloride, 7.5 parts ofsodium carbonate, 0.5 parts of potassium iodide and 160 parts of4-methyl-2-pentanone is stirred and refluxed for 70 hours. The reactionmixture is cooled and water is added. The organic layer is separated,dried, filtered and evaporated. The residue is taken up indiisopropylether, boiled with activated charcoal, filtered over hyfloand the filtrate is evaporated again. The oily free base is convertedinto its hydrochloride salt in the conventional manner in 2-propanol.The crystallized salt is filtered off and recrystallized from 2-propanol, yieldingcis-2,3,4,4a,5,6,7,7a-octahydro-lH-lpyrindine-l-propiono-2',6'-xylididehydrochloride; m.p. 202.2 C.

B. By repeating the process of Example IX-A, except that an equivalentquantity of 3,2,6'-trichloropropionanilide is substituted for thexylidide starting material used therein, there is obtainedcis-2,6'-dichloro-2,3,4,4a,5,6,7,7a-octahydro- 1 l-I- l -pyrindinel-propionanilide hydrochloride; m.p 203 C.

EXAMPLE X A mixture of 6.5 parts of 2-chloroaceto-2',6'-xylidide, 3.75parts of cis-octahydro-lH-l-pyrindine hydrochloride, 7.5

parts of sodium carbonate, 0.1 parts of potassium iodide and Y 200 partsof 4-methyl-2-pentanone is stirred and refluxed for 24 hours. Thereaction mixture is cooled and water is added. The organic layer isseparated, dried, filtered and evaporated. The residue is crystallizedfrom diisopropylether, yielding cis-2,3,4,-4a,5,6,7,7a-octahydro-lH-l-pyrindine-1-aceto-2,6- xylidide; m.p.l37.9 C.

EXAMPLE XI converted into the oxalate salt in dimethyl ketone, yieldingtrans-6'-chloro-2,3,4,4a,5,6,7,8,9,9a-decahydrol H-cycloheptalblpyrindine-l-propiono-o-toluidide oxalate; m.p. 151.1 C.

EXAMPLE XII A. A mixture of 6.9 parts of 3-chloro-2,4-propionoxylidide,3.75 parts of trans-octahydro-lH-l-pyrindine, 3.2 parts of sodiumhydrogen carbonate and parts of denatured ethanol is stirred overnightat a gentle reflux. The reaction mixture is evaporated. The residue isdivided between water and diisopropyl-ether. The organic phase isseparated, dried, filtered and evaporated. The base residue is convertedinto the oxalate salt in acetone. The salt is filtered off and dried,yielding trans-2,3,4,4a,5 ,6,7,7a-octahydrol H- l -pyrindinelpropiono-2',4-xylidide oxalate; m.p. l50.8 C.

B. The procedure of Example XII-A is followed, except that an equivalentquantity of 3-chloropropiono-2',5-xylidide is used in place of thexylidide starting material used therein, to yield the product:trans-2,3,4,4a,5,6,7,7a-octahydro-1H-lpyrindine-l-propiono-2,5'-xylidideoxalate; m.p. 166. 5 C.

EXAMPLE XIII A mixture of 7.6 parts of3,3'-dichloropropiono-o-toluidide, 3.75 parts oftrans-octahydro-lH-l-pyrindine, 3.2 parts of sodium hydrogen carbonateand 80 parts of denatured ethanol is stirred overnight at a gentlereflux. The reaction mixture is evaporated and the residue is dividedbetween water and diisopropylether. The organic layer is separated,dried, filtered and evaporated. The solid residue is crystallized fromdiisopropylether, yieldingtrans-3'-chloro-2,3,4,4a,5,6,7,7aoctahydro-lHl-pyrindine-l-propiono-o-toluidide;m.p. 91.7 C.

EXAMPLE XIV A mixture of 6.98 parts of 3-chloro-2',6'-propionoxylidide,5.28 parts of cis-decahydroquinoline, 8.4 parts of sodium hydrogencarbonate, 0.1 parts of potassium iodide and 200 parts of ethanol isstirred and refluxed for 2 days. The reaction mixture is evaporated. Theresidue is washed with water and extracted with ether. The extract isdried, filtered and the filtrate is acidified with 2-propanol previouslysaturated with gaseous hydrogen chloride. The crystallized salt isfiltered off and recrystallized twice from 2-propanol, yielding cis-3,4,4a,5,6,7,8,8a-octahydro-l(2H)quinolinepropiono-2,6- xylididehydrochloride; m.p. 227.5 C.

EXAMPLE XV A mixture of 7.6 parts of 3,4'-dichloropropiono-o-toluidide,3.75 parts of trans-octahydro-ll-I-l-pyrindine, 3.2 parts of sodiumhydrogen carbonate and 80 parts of denatured ethanol is stirredovernight at a gentle reflux. The reaction mixture is evaporated and theresidue is divided between water and diisopropylether. The latter phaseis separated, dried, filtered and evaporated. The oily base residue istaken up in diisopropylether and the solution is acidified with anexcess of 2-propanol previously saturated with gaseous hydrogenchloride. The precipitated salt is filtered off and dried, yieldingtrans-4'-chloro-2,3,4,4a,5 ,6,7,7a-octahydrol I-I- l-pyrindine-l-propiono-o-toluidide hydrochloride hydrate; m.p. l 56.6 C.

EXAMPLE XVI By repeating the procedure of Example XV, the followingcompounds of formula (I) can be prepared by starting with equivalentquantities of the appropriate starting material of formula (II) and theappropriate bicycloamine of formula (III), the latter in the cis ortrans form as indicated by the final product:

trans-2,3,4,4a,5,6,7,7a-octahydrol l-I- l -pyrindinelpropiono-2',3-xylidide hydrochloride, m.p. 77.2 C.; and

EXAMPLE XVII A suspension of 6.36 parts of 3-chloropropiono-2,6-xylidide, 4.74 parts of trans-decahydro-IH-cyclohepta-[b] pyridinehycrochloride and 5.04 parts of sodium hydrogen carbonate in 60 parts ofethanol is stirred and refluxed for 48 hours. The reaction mixture ispoured onto hydrochloric acid solution 2N and the mixture is extractedwith diisopropylether. The aqueous phase is alkalized with 50 percentsodium hydroxide solution and extracted with diidopropylether. Theorganic layer is dried and the solvent is evaporated in vacuo. The oilyfree base is converted into the oxalate salt in acetone. It is filteredoff and recrystallized twice: first from acetone and then from a mixtureof ethanol and acetone, yielding trans-2,3,4,4a,5,6,7,8,9,9a-decahydro-1H-cyclohepta[b]pyridinel -propiono-2',6-xylidide oxalate; m.p. 154.2c.

B. By repeating the procedure of Example XVII-A, except that vequivalent quantities of 3,6'-dichloropropiono-otoluidide and the cisform of the pyridine derivative are used,

the following product is obtained: cis-6-chloro-2,3,4,4 a,5,6,7,8,9,9a-decahydro-1H-cyclohepta[b]pyridine-lpropiono-o-toluidideoxalate; m.p. l6l.4 C.

EXAMPLE XVIII XIX A suspension of 6.36 parts of 3-chloropropiono-2',6'-xylidide, 4.74 parts of cis-decahydro-lH-cyclohepta-[b] pyridinehydrochloride and'5.04 parts of sodium hydrogen carbonate in 60 parts ofethanol is stirred and refluxed for 48 hours. The reaction mixture ispoured onto hydrochloric acid solution percent and the solution iswashed with diisopropylether. The aqueous phase is basified with a 50percent sodium .hydroxide solution and extracted with diisopropylether.The organic layer is dried and the solvent is removed in vacuo. Thesolid residue is crystallized from a mixture of petroleumether andbenzene and recrystallized from a mixture of hexane and petroleumether,yielding cis-2,3,4,4a,5,6,7,8,9,9a-decahydro-lH-cyclohepta[b]pyridinel-propiono-2',6'-xylidide;m.p. 108.5 C.

EXAMPLE XX A mixture of 7.4 parts of 3,6'-dichloropropiono-o-toluidide,

I 5 parts of trans-decahydroquinoline hydrochloride, 8.5 parts of sodiumhydrogen carbonate, 0.l parts of potassium iodide and 200 parts ofethanol is stirred and refluxed for 2 days. The reaction mixture iscooled, filtered and the filtrate is evaporated. The residue is dividedbetween water and diisopropylether. The organic layer is separated,dried, filtered and the filtrate is acidified with an excess of2-propanol previously saturated with gaseous hydrogen chloride. An oilysalt is separated, which solidifies on triturating in acetone. The solidsalt is filtered off and crystallized from a mixture of 2- propanol andacetone, yielding about 6.5 parts of crude trans-6'-chloro-3,4,4a,5,6,7,8,8a-octahydro-l(2H)quinolinepropiono-o-toluidide hydrochloride. The free base is liberated again and theproduct is purified over column-chromatography,

using a mixture of chloroform and methanol (9 l by volume) asmoving-liquid. The pure fractions are collected and converted again intothe hydrochloride salt. After crystallization from 2-propanol, about 1.8parts of pure trans-6'-chloro-3,4,4a,5,6,7,8,8a-octahydro-l(2H)quinolinepropiono-o-toluidide hydrochlorideare obtained; m.p. l90.8 C.

EXAMPLE XXI ,A mixture of 9.6 parts of ()-trans-6-chloro-2,3,4,4a,5,6,7,7a-octahydro-l H-l-pyrindine-l-propiono-o-toluidide, 6.96 parts of(+)-camphor-l0-sulfonic acid monohydrate and 40 parts of methyl ethylketone is heated till all solid enters solution. The solution isconcentrated and the residue ispoured onto diisopropylether. The wholeis heated till crystallization sets in. The formed precipitate isfiltered off (filtrate l is set aside) and dried in vacuo at 80 C.,yielding about 9 parts of the crude camphor-lO-sulfonate salt of(+)-trans-6'-chloro-2,3,4,4a,5,6,7,7a-octahydro-1H-l-pyrindine-l-propiono-otoluidide; m.p.137-l 39 C.; [a]D=+l9.5.

The crude fraction of 9 parts is crystallized several times from amixture of methyl ethyl ketone and diisopropylether (till constantrotation). The free base is then liberated in the conventional mannerand after crystallization from l2 parts of n-hexane, the product isfiltered off and dried in vacuo at 80 C., yielding about 0.5 parts of(+)-trans-6'-chloro-2,3,4,4a,5,6,7,7a-octahydro-1H-l-pyrindine-l-propiono-otoluidide; mp. 121 .2 C., [011D =+40.

The filtrate l, which was set aside and which contains the crudecamphor-lO-sulfonate salt of -)-trans-6'-chloro-2,3,4,4a,5,6,7,7a-octahydro-l H- l -pyrindinel-propiono-otoluidide, isconcentrated to dryness. The residue is stirred in 10 parts of ethylacetate. The whole is filtered and the filtrate is concentrated todryness, yielding 2 parts of the camphorl 0- sulfonate salt of(--)-trans-6-chloro-2,3,4,4a,5,6,7,7a-octahydro-lH-l-pyrindine-l-propion0+O-toluidide,[a]D 8. From the latter fraction, the free base is liberated in theconventional manner and crystallized from 7 parts of n-hexane, yieldingafter drying in vacuo at 80- C., about 0.1 parts of.()-trans-6-chloro-2,3,4,4a,5,6,7,7a-octahydro-l H- l -pyrindine-l-propiono-o-toluidide; m.p. l 20. 8C.; [a]D 4 1 .5.

EXAMPLE xxn This example demonstrates the synthetic method which may beused for making the starting compounds of formula (II).

A. To a solution of 81 parts of 2,6-dichloroaniline in 400 parts ofglacial acetic acid are added dropwise 70 parts of 2-chloropropionylchloride at a temperature of about 15 C. After theaddition is complete, the whole is stirred for 30 minutes at roomtemperature. Then there are added 500 parts of a solution of 200 partsof sodium acetate in 500 parts of water. The precipitated product isfiltered off, washed on the filter with water and dried, yielding3,2',6- trichloropropionanilide; m.p. 143 C.

B. To a stirred and cooled solution of 60.5 parts of 2,5- xylidine in400 parts of acetic acid are added dropwise 69.9 parts of3-chloropropionyl chloride, while keeping the temperature below 10 C.(external cooling). Upon completion, stirring at room temperature iscontinued for 2 hours. Then there are added 500 parts of a solution of200 parts of sodium acetate in 500 parts of water. The precipitatedproduct is filtered otf, washed with water and dissolved in chlorofonn.The

water, filtered off again, washed with water and dried. Afterrecrystallization from a mixture of diisopropylether and acetone,3-chloro-2',4-propionoxylidide is obtained; m.p. l 25.5 C.

D. To a stirred and cooled solution of l2l.l8 parts of 2,3- xylidine in800 parts of glacial acetic acid are added 96.1 parts of3-chloropropionylchloride at C. After stirring for 40 minutes, there areadded 400 parts of sodium acetate dis solved in 1,000 parts of water.The whole is stirred overnight. The precipitated product is filtered offand stirred for one hour in water. The product is filtered off again,washed once more with water and dried. After recrystallization from amixture of diisopropylether and acetone, 3-chloro-2',3'-propionoxylidide is obtained; mp. 955 C.

We claim:

1. A chemical compound selected from the group consisting of an N-(bicycloamino-alkanoyl)-aniline of the formula:

wherein R and R, are each a member selected from the group consistingofmethyl and chloro; Alk is a member selected from the group consistingof -CH and CH,CH and n is a whole integer from 1 to 3; and thepharmacologically active acid addition salts thereof.

2. A chemical compound selected from the group consisting of an N-(bicycloamino-alkanoyl)-aniline of the formula:

wherein each of R and R is a member selected from the group consistingof methyl and chloro, and n is the whole integer 1 or 2, and thetherapeutically active acid addition salts thereof.

3. Trans-3,4,4a,5,6,7,8,8a-octahydro-1(2H)-quinolineaceto-Z',6-xylidide.

4. Trans-2,3,4,4a,5,6,7,7a-oetahydro-l H-l-pyrindinelpropiono-2',6-xylidide.

5. Trans-6'-chloro-2,3,4,4a,5,6,7,7a-octahydrol H- l -pyrindinel-propiono-o-toluidide.

6.Trans-6'-chloro-3,4,4a,5,6,7,8,8a-octahydro-l(2H)quinolineaceto-o-toluidide.

7 Trans-2' ,6-dichloro-2,3 ,4,4a,5,6,7,7a-octahydrol H- lpyrindineJ-propionanilide.

8. Trans-2 ,6'-dichloro-3 ,4,4a,5 ,6,7,8 ,8a-octahydrol (2H)quinolinepropionanilide.

9. Cis-6-chloro-2,3,4,4a,5,6,7,7a-octahydro l H-I-pyrindine-l-propiono-o-toluidide.

10. Trans-2,3,4,4a,5,6,7,8,9,9a-decahydrol H-cyclohepta[b]pyridine-l-propiono-2',6-xylidide. oxalate.

l l. Cis-2,3 ,4,4a,5,6,7,8,9,9a-decahydrol H-cyclohepta[b]pyridine-1-propiono-2',6'-xylidide.

l2. Cis-6'-chloro3,4,4a,5,6,7,8,8a-octahydrol(2l-l)quinolinepropiono-o-toluidide.

l3. Trans-6-chloro-3,4,4a,5,6,7,8,8a-octahydrol2H)quinolinepropiono-o-toluidide.

l4. (-)-Trans-6'-chloro-2,3,4,4a,5,6,7,7a-octahydro-1 H-lpyn'ndine-l-propiono-o toluidide.

15. (+)-Trans-6'-chloro2,3,4,4a,5,6,7,7a-octahydro-1H-lpyrindine-l-propiono-o-toluidide.

2. A chemical compound selected from the group consisting of anN-(bicycloamino-alkanoyl)-aniline of the formula: 3.Trans-3,4,4a,5,6,7,8,8a-octahydro-1(2H)-quinolineaceto-2'',6''-xylidide.4.Trans-2,3,4,4a,5,6,7,7a-octahydro-1H-1-pyrindine-1-propiono-2'',6''-xylidide.5.Trans-6''-chloro-2,3,4,4a,5,6,7,7a-octahydro-1H-1-pyrindine-1-propiono-o-toluidide. 6.Trans-6''-chloro-3,4,4a,5,6,7,8,8a-octahydro-1(2H)quinolineaceto-o-toluidide.7. Trans-2'',6''-dichloro-2,3,4,4a,5,6,7,7a-octahydro-1H-1-pyrindine-1-propionanilide.
 8. Trans-2'',6''-dichloro-3,4,4a,5,6,7,8,8a-octahydro-1(2H)quinolinepropionanilide. 9.Cis-6''-chloro-2,3,4,4a,5,6,7,7a-octahydro-1H-1-pyrindine-1-propiono-o-toluidide. 10.Trans-2,3,4,4a,5,6,7,8,9,9a-decahydro-1H-cyclohepta(b)pyridine-1-propiono-2'',6''-xylidide. oxalate. 11.Cis-2,3,4,4a,5,6,7,8,9,9a-decahydro-1H-cyclohepta(b)pyridine-1-propiono-2'',6''-xylidide. 12.Cis-6''-chloro-3,4,4a,5,6,7,8,8a-octahydro-1(2H)quinolinepropiono-o-toluidide. 13.Trans-6''-chloro-3,4,4a,5,6,7,8,8a-octahydro-1(2H)quinolinepropiono-o-toluidide. 14.(-)-Trans-6''-chloro-2,3,4,4a,5,6,7,7a-octahydro-1H-1-pyrindine-1-propiono-o-toluidide. 15.(+)-Trans-6''-chloro-2,3,4,4a,5,6,7,7a-octahydro-1H-1-pyrindine-1-propiono-o-toluidide.